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標題: The Role of PITX2B in Non-Small-Cell Lung Cancer
作者: 黃宇涵
Huang, Yu-Han
關鍵字: tumor suppressor;異構蛋白;HLJ-1;PITX2;NLS;siRNA;轉錄因子;基因靜默;自噬現象
出版社: 分子生物學研究所
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Non-small-cell lung cancer is one of the most common cancers in the world. It is a leading cause of cancer death with high risk. In our previous study demonstrated that knockdown of HLJ1, a novel tumor suppressor gene, increased PITX2 expression, suggesting that PITX2 may promote the tumorigenic ability of non-small-cell lung cancer. PITX2 (paired-like homeodomain transcription factor 2) is involved in the development of the eye, tooth and abdominal organs. This gene is a member of the bicoid-homeodomain class of transcription factors implicated in controlling left-right asymmetry during organogenesis. Three transcript variants encoding distinct isoforms have been identified for this gene. In our study, we found that PITX2B was the major isoform frequently expressed in the aggressive lung cancer cell lines. Furthermore, overexpression of PITX2B in CL1-0 could enhance the ability of invasion、migration、proliferation and tumorigenesis in human non-small-cell lung cancer. In addition, we performed site-direct mutagenesis at the NLS (nuclear localization signal) of PITX2B to generate the PITX2B mutants and introduced these constructs to lung cancer cells. Interesting, the results demonstrated that NLS is important for PITX2B to promote cell migration and colony formation activity. However, the underlying molecular mechanism remains to be verified. . On the other side, we used the siRNA (small interference RNA) to silence the expression of PITX2 mRNA, and noticed that silence of PITX2 could induce cell autophagy and lead to cell death. Taken together, the expression of PITX2B is important for non-small-cell lung cancer progression.

非小細胞肺癌是世界上最常見的癌症之一,是具有極高死亡率之惡性腫瘤,在之前的研究中發現,當靜默 (silence) tumor suppressor HLJ-1的表現後會增加 PITX2的表現量,由此相關性推測PITX2基因可能與促進非小細胞肺癌的發生有著密切的關係。PITX2 (paired-like homeodomain transcription factor 2)參與在眼睛、牙齒和腹腔器官的發育,是bicoid-homeodomain 轉錄因子的一員,特別在於調控生物體的左右對稱。
PITX2具有三個異構蛋白(isoforms),在我們的研究中發現在肺癌細胞株中,PITX2基因的表現是以PITX2B這個異構蛋白為主,因此我們將PITX2B基因在CL1-0肺癌細胞株中大量表現,發現PITX2B大量表現會促進非小細胞肺癌的侵襲、移動、增生和腫瘤生成的能力。我們進一步將PITX2B的進核訊號NLS (nuclear localization signal) 進行點突變,藉由改變PITX2B NLS的結構阻止PITX2B進入細胞核,並將PITX2B突變之基因在CL1-0肺癌細胞株中大量表現,實驗結果發現PITX2B之NLS對於促進癌細胞的移動和增生能力是非常重要的。未來我們會繼續探討PITX2B影響癌細胞侵襲和轉移能力之pathway,藉此確認PITX2B基因影響癌細胞行為之路徑。另一方面,我們也利用siRNA(small interference RNA)將PITX2基因之mRNA靜默,我們觀察到當PITX2基因靜默時會誘發細胞的自噬現象,導致細胞死亡。由以上結果可以得知PITX2B對於促進非小細胞肺癌的發生扮演著非常重要的角色。
其他識別: U0005-1208201114374200
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